ABSTRACT
RATIONALE: Recently a new 5-hydroxytryptamine1B (5-HT1B)-receptor antagonist, AR-A000002, was described. It was shown that this compound dose dependently increased 5-HT metabolism and release in guinea pig brain following a single injection. OBJECTIVES: The present study investigated effects of 3 weeks twice-daily treatment of guinea pigs with the 5-HT1B-receptor antagonist AR-A000002 on the serotonergic neurons and receptor densities. METHODS: Guinea pigs were injected subcutaneously with AR-A000002, citalopram or saline twice daily for 3 weeks. Groups of animals were treated with challenge doses of AR-A000002 or saline 24 h after the last chronic treatment (citalopram group 48 h) and sacrificed 2 h thereafter. The effect on 5-HT metabolism and 5-HT release was assessed. Plasma and brain concentrations of AR-A000002 were analysed. The effects on binding of [3H]8-OH-DPAT to 5-HT1A receptors, [3H]GR125743 to 5-HT(1B/1D) receptors, [3H]ketanserin to 5-HT2A receptors, and [3H]prazosin to alpha1-adrenoceptors were determined. RESULTS: Repeated treatment of guinea pigs with AR-A000002 did not change the 5-HT(1B/1D), 5-HT1A, 5-HT2A or alpha1-adrenergic receptor densities. Following repeated treatment of guinea pigs for 3 weeks with AR-A000002, the 5-HT1B receptors were still receptive to a challenge with the same compound. Thus, an increase in the 5-HIAA/5-HT ratio and 5-HT release was seen following challenge doses of AR-A000002. No difference in the plasma and brain concentrations of AR-A000002 was found between the sub-chronic treated AR-A000002 and saline-treated guinea pigs. CONCLUSIONS: It is concluded that AR-A000002 is a 5-HT1B receptor antagonist, which enhances persistently the serotonergic neurotransmission in guinea pig brain.
